Azithromycin (9-deoxo-9a-aza-9a-methyl-9a-homoerythromycin A; CAS # 83905-01-5) is an antibiotic that interferes with protein synthesis in bacteria by binding to the 50S ribosomal subunit. Azithromycin is often used to treat respiratory infections, and is marketed under the tradename ZITHROMAX® (Pfizer Inc., New York, N.Y.). Azithromycin has the following chemical structure:

At least two crystalline forms of azithromycin have been reported, azithromycin dihydrate and azithromycin monohydrate. U.S. Pat. No. 6,268,489 (the '489 patent) discloses azithromycin dihydrate as a crystalline form of azithromycin that contains two molecules of water per molecule of azithromycin. The '489 patent further describes that azithromycin dihydrate is stable and non-hygroscopic. Because of these properties, azithromycin dihydrate is used commercially. The '489 patent discloses azithromycin monohydrate as a crystalline form of azithromycin that contains one molecule of water per molecule of azithromycin. The '489 patent further states that azithromycin monohydrate is unstable and hygroscopic.
U.S. Publication No. 2004/0053862 A1 (the '862 publication) discloses an azithromycin monohydrate form having a water content from 4.0 to 6.0% w/w of water that is stable and non-hygroscopic. In the '862 publication, azithromycin monohydrate is prepared by the addition of an alkaline solution to a hydrochloric acid (HCl) solution of azithromycin; howver, it should be noted that azithromycin is reported to be unstable under acidic conditions (See, e.g., U.S. Pat. No. 6,586,576 B2).
There is a continuing need for a process of preparing crystalline azithromycin monohydrate that is useful for commercial purposes. It is desirable to prepare a crystalline azithromycin monohydrate that is substantially free of organic solvents and is stable, i.e., does not degrade.